2-hydroxy-2-(3-acyl-4-oxoalkyl)-6-vinyl-tetrahydropyrans and tautomers

ABSTRACT

2-HYDROXY-2-(3-ACYL-4-OXOALKYL) - 6 - VINYLTETRAHYDROPYRANS AND TAUTOMERS THEREOF ARE INTERMEDIATES USEFUL IN THE PREPARATION OF PHARMACEUTRICALLY VALUABLE STEROIDAL COMPOUNDS. PREPARATION OF SUCH COMPOUNDS FROM 2-(2&#39;&#39;SUBSTITUTED AMINOETHYL)-2-HYDROXY - 6 - VINYLTETRAHYDROPYRANS AND THEIR ALKYL SUBSTITUTED ANALOGS ARE DESCRIBED.

United States Patent Office $553112 readily understood by reference tothe following reaction 3,751,433 scheme:2-HYDROXY-2-(3-ACYL4-OXQALKYL)-6-VINYL- REACTION SCHEME TETRAHYDROPYRANSAND TAUTOMERS Gabriel Saucy, Essex Fells, N.J., assiguor to Hoffmann- LaRoche Inc., Nutley, NJ. 5 No Drawing. Original application Jan. 19,1970, Ser. No. l R I 4,026, now Patent No. 3,671,539. Divided and this0H application Mar. 29, 1972, 521'. No. 239,369 O Int. Cl. C07d 7/04 0US. Cl. 268-3459 3 Claims 10 R1 HO R3 ABSTRACT on THE DISCLOSURE l E OHR.

2-hydroxy-2-(3-acyl-4-oxoalkyl) 6 vinyltetrahydro- R7 RE 1 pyrans andtautomers thereof are intermediates useful in (a) the preparation ofpharmaceutically valuable steroidal N compounds. Preparation of suchcompounds from 2-(2- substituted aminoethyl) -2-hydroxy 6vinyltetrahydro- R1 0 RELATED APPLICATIONS Y This application is adivisional of copending applica- H 2 O E tion Ser. No. 4,026, filed Jan.19, 1970 and now US. Pat. No. 3,671,539, entitled Preparation ofAminoethyl Isoxr azolyl Substituted Tetrahydropyrans and IntermediatesTherefor. NHOH/ BRIEF DESCRIPTION OF THE INVENTION (b) The presentinvention relates to novel processes useful X in the preparation ofcompounds of the following formula R4 5H1 OH pyrans and their alkylsubstituted analogs are described.

OH i Ra HON Ra IR 0 NOH NOH R IV 7 \OABa 1 40 o) where R R and R areselected from the group con- 1) sisting of hydrogen and lower alkyl; R,is selected from I the group consisting of hydrogen, lower alkyl, loweralkyl- N R5 aryl and aralkyl; R taken independently is hydrogen or loweralkyl; R taken independently is lower alkyl or Ammcmhol aralkyl; and Rand R taken together with the adjacent nitrogen atom form a 5 or 6membered saturated hetero- HO cyclic ring including at the most oneadditional hetero atom selected from the group consisting of nitrogenand include both branched and straight chain hydrocarbon radicals havingfrom 1 to 7, preferably 1 to 4 carbon atoms. Examples of suitable loweralkyl groups include methyl, ethyl, propyl and butyl. Examples ofsuitable R R4 1 lower alkyl aryl groups include tolyl, xylyl and thelike. 0 l 1 N oxygen. R

i 9, 5 As used herein the term lower alkyl is meant to O /\N The termaralkyl is meant to include groups such as phenyl-lower alkyl, e.g.,benzyl and phenylethyl. a R The processes of the present inventionutilized in the a preparation of compounds of Formula I above are more v(VI) (I) where R R R R R and R are as above; and R and R are defined asR and R respectively both independently and when taken together.

In step (a) of the process of the present invention compounds ofFormulae IIa or IIb are reacted with a diketone compound of thefollowing formula RI IR where R and R are as above.

The reaction sequence outlined in the above reaction scheme utilizeseither vinyl ketones of the structure shown in Formula IIa or aminoketones of Formula IIb as alternative starting materials. It is to benoted that when the amino ketones of Formula IIb are placed in solutionsome of this compound is converted to the vinyl ketone of Formula IIa.Either type of compound or mixtures thereof can be used as startingmaterial. The amino moiety represented by R R N in Formula IIb can be alower alkyl amine such as methylamine, ethylamine, propylamine,n-butylamine, hexylamine, etc., preferably n-butylamine; aralkylaminessuch as a-methylbenzylamine or amines of complex molecules such as, forexample, dehydroabietylamine. Suitable amino groups also include.di-lower alkylamines which may optionally contain additionalsubstituents on the alkyl group, e.g., phenyl or cyclic amino groups.Examples of such di-substituted amines include dimethylarnine,diethylamine, methylethylamine and the like. Diethylamine is preferred.The amino moiety may also comprise a cyclic group optionally containingah additional hetero atom in the ring. Examples of cyclic amines includepyrrolidine and piperidine. Morpohline is an example of a cyclic aminehaving an additional hetero atom.

The preparation of starting materials of Formula 11b is described insome detail in U.S. patent application Ser. No. 834,547, filed June 18,1969, inventor Gabriel Saucy, and also in Ser. !No. 830,491, filed June4, 1969, inventor Gabriel Saucy.

This reaction is conveniently conducted at a temperature in the range offrom about 20 to 200 C., most preferably at the reflux temperature of asuitably high boiling inert organic solvent. Suitable inert organicsolvents for this purpose include the aromatic hydrocarbons, mostpreferably xylene or toluene. The reaction product obtained is acompound of Formula III which as indicated in the above reaction schemeis believed to exist as an equilibrium mixture of the two structuresshown. Infrared and nuclear magnetic resonance spectra indicate that apredominant form in this equilibrium is the enol form. However, it isunderstood that this equilibrium can be shifted by changes in theambient conditions such as temperature, selection of solvent system, andthe pH of the solution. The exact structure of compounds of Formula IIIis not believed to be critical to the practice of the present inventionsince both of the indicated forms are useful in further transformations.It is also possible to use compounds of Formula III in crude form forsuch further transformations.

Compounds of Formula IH are then treated with hydroxylamine or a saltthereof in step (b) to yield mixed isomers of the bisoxime of FormulaIV. This reaction is conveniently conducted at a temperature in therange of from about 20 to 100 C., most preferably at about roomtemperature. Suitable salts of hydroxylamine include the mineral acidsalts of hydroxylamine, most preferably the hydrochloride salt. Thisreaction is most desirably conducted in the presence of an organic base,most preferably a tertiary amine such as a tri-lower alkylamine, e.g.,triethylamine.

In step (c) the above bis-oxime of Formula IV is converted by heating tothe isoxazole oxime of Formula V. Suitable solvents for use in thistransformation step include organic solvents having a boiling pointabove about (VII) 50-200" C., and include, for example, aromatichydrocarbons such as toluene and xylene. Generally, the reaction is mostdesirably conducted at the reflux temperature of the solvent medium.Compounds of Formula V need not be purified prior to undergoing the nextprocess step in the reaction scheme.

In step (d) compounds of Formula V are subjected to aqueous acidhydrolysis to yield compounds of Formula VI. It is understood thatcompounds of Formula VI may exist as an equilibrium tautomeric mixtureof the indicated tetrahydropyranol form and the corresponding openhydroxy ketone compounds. 'Particularly suitable aqueous acids for usein the above hydrolysis step include the mineral acids, e.g., sulfuricacid, hydrochloric acid, phosphoric acid and the like. A most preferredaqueous acid for this purpose is dilute sulfuric acid, e.g., 1 -Nsulfuric acid. The hydrolysis reaction may conveniently be conducted ata temperature in the range of from about 0 to C., most preferably atabout room temperature. The reaction may also be conducted in thepresence of an added inert organic solvent. Suitable solvents for thispurpose include ketones such as acetone and methyl ethyl ketone. Acetoneis the solvent of preference for this purpose.

In the final reaction step, step (e), compounds of Formula VI areconverted to compounds of Formula I by treatment of the former compoundswith a reaction medium comprising a metal alkoxide and an organic amine.Suitable metal alkoxides useful in the practice of this reaction stepinclude the aluminum lower alkoxides and sodium lower alkoxides, e.g.,aluminum isopropoxide and sodium methoxide. Aluminum isopropoxide is theagent of greatest preference in this reaction step.

The amine compound may be represented by the formula R R NH. Examples ofsuitable amines include the lower alkylamines such as methylamine,ethylamine, propylamine, n-butylamine, hexylamine, etc., most preferablyn-butylamine; alkylamines such as a-methylbenzylamine or amines ofcomplex molecules such as, for example, dehydroabietylamine. Suitableamines also include the di-lower alkylamines which may optionallycontain additional substituents on the alkyl group, e.g., phenyl orcyclic amino groups. Examples of such disubstituted amines includedimethylamine, diethylamine, methylethylamine and the like. Diethylamineis preferred. The amine compound may also comprise a cyclic groupoptionally containing an additional hetero atom in the ring. Examples ofcyclic amines include pyrrolidine and piperidine. Morpholine is anexample of a cyclic amine having an additional hetero atom.

In a particularly preferred embodiment optionally active amines areemployed in step (e). A highly desirable amine for this purpose is()-a-phenethylamine. Use of optically active amines in reaction step (e)results in the formation of mixtures of diastereoisomers of compounds ofFormula I. Fractional crystallization of this mixture results in thepreparation of optically active compounds of Formula I which areeminently suitable as intermediates in the preparation of opticallyactive steroids of valuable pharmacological properties.

Temperature conditions useful in the practice of reaction step (e)include a temperature in the range of from about 0 C. to the refluxtemperature of the reaction medium, most preferably at about the refluxtemperature of the reaction medium. This reaction may conveniently beconducted in the presence of an inert organic solvent. Suitable solventsfor this purpose include aromatie hydrocarbons such as benzene, tolueneand xylene.

While it is highly desirable to utilize the metal alkoxide and theorganic amine simultaneously in a single reaction medium to effectuatethe conversion of compounds of Formula VI to compounds of Formula I itis also possible to add these reagents stepwise. In such event anintermediate compound having the structure represented by Formula VIIIis believed to be obtained in the reaction mixture.

OHI

Rs I

. R, where R R R and R are as above.

A by-product obtained from the process of step (e) is the isomericS-hydroxy compound of the formula:

(VIII) H (no where R R R R R and R are as above.

Compounds of Formula :IX can be separated from the desired product ofFormula I by chromatography over alumina. The compounds of Formula 1Xcan be isomerized to give a mixture containing a major amount ofcompounds of Formula I by treatment of the former compounds with themetal alkoxide under the conditions used in step (e).

The compounds of Formulae III, IV, V and VI above are novelintermediates and as such form a part of the present invention.Preferred embodiments of the process and compound aspects of the presentinvention are obtained when R; and R both are hydrogen, R and R both arelower alkyl, R is hydrogen or lower alkyl, most preferably ethyl, R islower alkyl, most preferably ethyl or aralkyl, most preferablyphenethyl, and R and R both are lower alkyl, most preferably ethyl.

Starting materials of Formula 11 may be prepared in accordance withprocedures described in detail in US. patent application Ser. No.818,142, filed Apr. 21, 1969, and now -U.S. Pat. No. 3,631,039, title,Preparation of Tricyclic Intermediates, inventors, David Andrews andGabriel Saucy.

The conversion of compounds of Formula I into racemic or opticallyactive 19-norsteroids of known pharmacological value is described indetail in U.S. patent application Ser. No. 778,314, filed Nov. 22, 1968,and now US. Pat. No. 3,700,661, inventors Gabriel Saucy and John WilliamScott.

The present invention will be more clearly understood by reference tothe following examples.

EXAMPLE 1 Preparation of 2-hydroxy-2-(3-acetyl-4-oxopentyl-6-vinyltetrahydropy1'an Into a 500 ml. flask equipped with condenser,thermometer, nitrogen inlet and magnetic stirrer were placed 45.4 g. of2-[2'-diethylaminoethyl]-2-hydroxy-6-vinyltetrahydropyran, 40.0 g. of2,4-pentaneidone and 250 m1. of toluene. The mixture was degassed,placed under nitrogen and heated 3 /2 hours at reflux. At this point,20.0 g. of 2,4-pentanedione was added and heating at reflux wascontinued three more hours. The solution was then cooled, transferred toa round bottom flask and evaporated in vacuo C., 15 mm. Hg) withagitation. The resulting oil was then placed under high vacuum at 50 C.with agitation to ensure removal of the last traces of excess2,4-pentanedione. There was thus obtained the above-titled product in ayield of 63.2 g.

as an orange-red oil. A sample of this material was purified bychromatography on silica gel. UV and NMR analysis showed the B-diketonesystem to be enolic to the extent of about 20 percent (in chloroform at25 C.).

Calcd. for C H Q, (percent): C, 66.11; H, 8.72. Found (percent): C,66.27; H, 8.63.

EXAMPLE 2 Preparation of3-acetyl-10-hydroxy-Z,7-dihydroxyiminododec-ll-ene Into a 2-liter flaskequipped with mechanical stirrer were placed 63.2 g. of crude2-hydroxy-2-(3-acetyl-4-oxopentyl)-6-vinyltetrahydropyran, 450 ml. ofabsolute ethanol, 89 ml. of triethylamine and 28.0 g. of hydroxylaminehydrochloride. A slight temperature rise occurred when the hydrochloridewas added. The slurry was stirred at room temperature for 8 hours as thehydrochloride gradually dissolved. The resulting solution was evaporatedto dryness with agitation at 60 C. and 15 mm. Hg. Small portions oftoluene were added to the residue to remove the last traces of ethanol.The resulting pasty mixture comprised the above-titled product andtriethylamine hydrochloride and can be utilized in crude form in furthertransformations.

EXAMPLE 3 Preparation of 1-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-3-hydroxyimino-non-8-ene The crude mixture of the dioxime andtriethylamine hydrochloride obtained in Example 2 was combined with 700ml. of toluene and the mixture was degassed. It was then placed undernitrogen and heated at reflux for three hours. The resulting slurry wascooled, stirred with 500 ml. of water and the mixture was transferred toa separatory funnel with ether rinsing. The aqueous phase was separatedand extracted twice with ether. The combined ether extracts and toluenelayer were then extracted with 2X 50 ml. and then 1X 25 ml. of Claisensalkali which is made by dissolving 70 g. of potassium hydroxide in 50ml. of water, cooling, adding 200 ml. of methanol and cool ing againbefore use. The combined alkali extracts were washed with 3 X 50 ml. of1:1 ether/benzene mixture and the washings Were discarded. The washedalkali solution was then combined with an equal volume of methylenechloride in an Erlenmeyer flask and neutralized by the dropwise additionof acetic acid with stirring and external cooling to maintain thetemperature at 25 C. or less. When pH 6 was obtained, the mixture wastransferred to a separatory funnel and 125 ml. of saturated brine wasadded. At the start of shaking, the organic layer was separated and theaqueous phase was extracted twice with ml. portions of methylenechloride. The combined organic phase and methylene chloride extractswere washed with 100 ml. of 1:1 saturated brine/saturated sodiumbicarbonate solutions, dried over anhydrous sodium sulfate and vacuumevaporated at 60 C. and 15 mm. Hg with agitation to give 38.2 g. of 1(3,5-diethyl 4-isoxazolyl)-7-hydroxy-3-hydroxyirnino-non-8-ene as abrown viscous oil. A sample of this product was purified by columnchromatography and then analyzed. Based on the IR and NMR spectra, theoxime group is present in both its syn and anti form.

Calcd. for C I-1 N 0 (percent): C, 63.13; H, 8.33; N, 10.52. Found(percent): C, 63.26; H, 8.50; N, 10.33.

EXAMPLE 4 Preparation of1-(3,5-dimethyl-4-isoxazolyl)-7-hydroxynon-8-en-3-one A total of 38.2 g.of crude1-(3,5-dimethyl-4-isoxazolyl)-7-hydroxy-3-hydroxyimino-non-8-ene wasdissolved in 225 ml. of acetone and 100 ml. of 1 N sulfuric acid wasadded with stirring. The solution was allowed to stand at roomtemperature for two days and was then vacuum evaporated at 35 C. and15mm. Hg to remove the organic solvent. The resulting aqueous emulsionwas par-' titioned between 250 ml. of water and 200 ml. of methyl: enechloride. The aqueous phase was extracted with 100 ml. of methylenechloride and the combined organic extracts were washed with 100 ml. of1:1 saturated brine/ saturated sodium bicarbonate solution. The organicphase was dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to give 31.8 g. of crude product as a brown oil. The productcan be purified by passage through a chromatographic column packed withalumina (activity III) and using benzene as eluting solvent until firstproduct appears and then eluting the remainder of the product from thecolumn using a 9:1 benzene/ether mixture. A sample of this product wasfurther purified by short-path distillation; B.P. -179 C. at 0.2 mm. Hg.Calcd. for C H NO (percent): C, 66.91; H, 8.42; N, 5.57. Found(percent): C, 66.88; H, 8.40; N, 5.32.

EXAMPLE 5 Preparation of 2- (diethylarnino -6- (2- 3,5-dimethyl-4-isoxazolyl] -ethy1) -tetrahydropyran- 2-ol A total of 100 mg. of1-(3,5-dimethyl-4-isoxazolyl)-7- hydroxy-non-8-en-3-one was allowed toreact with 25 mg. of aluminum isopropoxide and 0.1 ml. of diethylaminein 5 ml. of refluxing toluene for one and one-half hours under anitrogen atmosphere. After cooling, the reaction mixture waschromatographed on 5 g. of silica gel using benzene-diethylamine (99:1)and (19:1) mixtures as eluants. A total of 127.8 mg. of product as anoil was obtained upon evaporation of the first 6x 5 m1. fractions. Thismaterial was rechromatographed on 3.6 g. of alumina (activity III).Elution with benzene and benzene containing 2% of diethylamine (total of6x 4 ml.) gave pure product 2-(diethylamine)-6-(2-[3,5-dimethyl-4-isoxazolyl]-ethyl)-tetrahydropyran-2-olas an oil after evaporation of the solvents in vacuo. A total of 95 mg.of desired product was obtained 'in this fashion. The IR spectrum ofthis material exhibited typical bands at 1640 cm.- (isoxazole moiety),1710 cm. (carbonyl) and -3400 (bonded OH). The compound had a UV maximum(in ethanol) at 220 mu, e=5350.

Elution of the column with more benzene-diethylamine aflforded theconsiderably more polar isometric S-hydroxy compound. When this materialwas refluxed for three hours withaluminum isopropoxide indiethylaminebenzene a mixture of the desired Z-hydroxy and S-hydroxycompounds in the respective ratio of albout.2:1 was obtained. Thismixture may be separated by using the chromatographic procedure above.

hydroxy-non-S-en-B-one was reacted with 300 mg. of aluminum isopropoxideand 908 mg. of ()-phenethylamine in 36 ml. of refluxing toluene for 1hour under a nitrogen atmosphere. The reaction mixture was washed firstwith water and then with 3 N hydrochloric acid (3X 20 ml.).'The acidextract was washed twice with benzene and then treated with 10 N sodiumhydroxide and ice to bring the pH to about 11. Extraction with 3 x 50ml. of benzene, washing with brine, drying over sodium sulfate, followedby filtration and evaporation to dryness afforded 1.50 g. of crudeproduct as an oil. This material was chromatographed on g. of alumina(activity III). Elution with benzene (75 ml. fractions) gave, afterevaporation of the solvent, 518 mg. of product obtained from fractions3-9 of thin-layer chromaftographically pure product (a mixture of twodiastereoisomers) and- .289 mg. of slightly impure product.

The pure material (518 mg.) was resolved by crystallization fromisopropyl ether to afford optically pure (l-diastereoisomer) 2S,6 R2-[2-(S-a-phenethylamino) ethyl]-6-[2-(3,5-dimethyl-4 isoxazolyl)ethyl]tetrahydropyran-2-ol; M.P. 68-71.5 C.; @1 -20.02 (6.: 1.0 in benzene).

What is claimed is:

1. A compound of the formula No references cited.

NORMA s. MILESTONE, Primary Examiner

